Method of inhibiting matrix metalloproteinases

Abstract

The present invention relates to a method of inhibiting matrix metalloproteinases using compounds that are dibenzofuran sulfonamide derivatives having the Formula I More particularly, the present invention relates to a method of treating diseases in which matrix metalloproteinases are involved such as multiple sclerosis, atherosclerotic plaque rupture, restenosis, aortic aneurism, heart failure, periodontal disease, corneal ulceration, burns, decubital ulcers, chronic ulcers or wounds, cancer metastasis, tumor angiogenesis, arthritis, or other autoimmune or inflammatory diseases dependent upon tissue invasion by leukocytes.

What is claimed is:  
     
       1. A method of treating atherosclerotic plaque rupture, the method comprising administering to a patient having an atherosclerotic plaque at risk for rupture a therapeutically effective amount of a compound of Formula I                    
       wherein M is a natural (L) alpha amino acid derivative having the structure                    
       X is O, S, S(O) n , CH 2 , CO, or NR Q ;  
       R Q  is hydrogen, C 1 -C 6  alkyl, or —C 1 -C 6  alkyl-phenyl;  
       R is a side chain of a natural alpha amino acid;  
       R 1  is C 1 -C 5  alkoxy, hydroxy, or —NHOR 5 ;  
       R 2  and R 4  are independently hydrogen, —C 1 -C 5  alkyl, phenyl —NO 2 , halogen, —OR 5 , —CN, —CO 2 R 5 , —SO 3 R 5 , —CHO, —COR 5 , —CONR 5 R 6 , —(CH 2 ) n NR 5 R 6 , —CF 3 , or —NHCOR 5 ;  
       each R 5  and R 6  are independently hydrogen or C 1 -C 5  alkyl; and n is 0 to 2, and the pharmaceutically acceptable salts, esters, and amides thereof, wherein the esters thereof are selected from C 1 -C 6  alkyl esters, C 5 -C 7  cycloalkyl esters, and arylalkyl esters and the amides thereof are derived from ammonia, primary C 1 -C 6  alkyl amines, secondary C 1 -C 6  dialkyl, and 5- and 6-membered heterocyclic amines containing one nitrogen atom; and wherein the group S(═O) 2 M is optionally bonded to the 1-, 2- , or 3-position of Formula I.  
     
     
       2. A method of treating or preventing aortic restenosis, the method comprising administering to a patient having aortic restenosis or at risk of having aortic restenosis a therapeutically effective amount of a compound of Formula I                    
       wherein M is a natural (L) alpha amino acid derivative having the structure                    
       X is O, S, S(O) n , CH 2 , CO, or NR Q ;  
       R Q  is hydrogen, C 1 -C 6  alkyl, or —C 1 -C 6  alkyl-phenyl;  
       R is a side chain of a natural alpha amino acid;  
       R 1  is C 1 -C 5  alkoxy, hydroxy, or —NHOR 5 ;  
       R 2  and R 4  are independently hydrogen, —C 1 -C 5  alkyl, phenyl —NO 2 , halogen, —OR 5 , —CN, —CO 2 R 5 , —SO 3 R 5 , —CHO, —COR 5 , —CONR 5 R 6 , —(CH 2 ) n NR 5 R 6 , —CF 3 , or —NHCOR 5 ;  
       each R 5  and R 6  are independently hydrogen or C 1 -C 5  alkyl; and  
       n is 0 to 2, and the pharmaceutically acceptable salts, esters, and amides thereof, wherein the esters thereof are selected from C 1 -C 6  alkyl esters, C 5 -C 7  cycloalkyl esters, and arylalkyl esters and the amides thereof are derived from ammonia, primary C 1 -C 6  alkyl amines, secondary C 1 -C 6  dialkyl, and 5- and 6-membered heterocyclic amines containing one nitrogen atom; and wherein the group S(═O) 2 M is optionally bonded to the 1-, 2-, or 3-position of Formula I.  
     
     
       3. A method of treating aortic aneurism, the method comprising administering to a patient having aortic aneurism a therapeutically effective amount of a compound of Formula I                    
       wherein M is a natural (L) alpha amino acid derivative having the structure                    
       X is O, S, S(O) n , CH 2 , CO, or NR Q ;  
       R Q  is hydrogen, C 1 -C 6  alkyl, or —C 1 -C 6  alkyl-phenyl;  
       R is a side chain of a natural alpha amino acid;  
       R 1  is C 1 -C 5  alkoxy, hydroxy, or —NHOR 5 ;  
       R 2  and R 4  are independently hydrogen, —C 1 -C 5  alkyl, phenyl —NO 2 , halogen, —OR 5 , —CN, —CO 2 R 5 , —SO 3 R 5 , —CHO, —COR 5 , —CONR 5 R 6 , —(CH 2 ) n NR 5 R 6 , —CF 3 , or —NHCOR 5 ;  
       each R 5  and R 6  are independently hydrogen or C 1 -C 5  alkyl; and  
       n is 0 to 2, and the pharmaceutically acceptable salts, esters, and amides thereof, wherein the esters thereof are selected from C 1 -C 6  alkyl esters, C 5 -C 7  cycloalkyl esters, and arylalkyl esters and the amides thereof are derived from ammonia, primary C 1 -C 6  alkyl amines, secondary C 1 -C 6  dialkyl, and 5- and 6-membered heterocyclic amines containing one nitrogen atom; and wherein the group S(═O) 2 M is optionally bonded to the 1-, 2-, or 3-position of Formula I.  
     
     
       4. A method of treating periodontal disease, the method comprising administering to a patient having periodontal disease a therapeutically effective amount of a compound of Formula I                    
       wherein M is a natural (L) alpha amino acid derivative having the structure                    
       X is O, S, S(O) n , CH 2 , CO, or NR Q ;  
       R Q  is hydrogen, C 1 -C 6  alkyl, or —C 1 -C 6  alkyl-phenyl;  
       R is a side chain of a natural alpha amino acid;  
       R 1  is C 1 -C 5  alkoxy, hydroxy, or —NHOR 5 ;  
       R 2  and R 4  are independently hydrogen, —C 1 -C 5  alkyl, phenyl —NO 2 , halogen, —OR 5 , —CN, —CO 2 R 5 , —SO 3 R 5 , —CHO, —COR 5 , —CONR 5 R 6 , —(CH 2 ) n NR 5 R 6 , —CF 3 , or —NHCOR 5 ;  
       each R 5  and R 6  are independently hydrogen or C 1 -C 5  alkyl; and  
       n is 0 to 2, and the pharmaceutically acceptable salts, esters, and amides thereof, wherein the esters thereof are selected from C 1 -C 6  alkyl esters, C 5 -C 7  cycloalkyl esters, and arylalkyl esters and the amides thereof are derived from ammonia, primary C 1 -C 6  alkyl amines, secondary C 1 -C 6  dialkyl, and 5- and 6-membered heterocyclic amines containing one nitrogen atom; and wherein the group S(═O) 2 M is optionally bonded to the 1-, 2-, or 3-position of Formula I.  
     
     
       5. A method of treating corneal ulceration, the method comprising administering to a patient having corneal ulceration a therapeutically effective amount of a compound of Formula I                    
       wherein M is a natural (L) alpha amino acid derivative having the structure                    
       X is O, S, S(O) n , CH 2 , CO, or NR Q ;  
       R Q  is hydrogen, C 1 -C 6  alkyl, or —C 1 -C 6  alkyl-phenyl;  
       R is a side chain of a natural alpha amino acid;  
       R 1  is C 1 -C 5  alkoxy, hydroxy, or —NHOR 5 ;  
       R 2  and R 4  are independently hydrogen, —C 1 -C 5  alkyl, phenyl —NO 2 , halogen, —OR 5 , —CN, —CO 2 R 5 , —SO 3 R 5 , —CHO, —COR 5 , —CONR 5 R 6 , —(CH 2 ) n NR 5 R 6 , —CF 3 , or —NHCOR 5 ;  
       each R 5  and R 6  are independently hydrogen or C 1 -C 5  alkyl; and  
       n is 0 to 2, and the pharmaceutically acceptable salts, esters, and armides thereof, wherein the esters thereof are selected from C 1 -C 6  alkyl esters, C 5 -C 7  cycloalkyl esters, and arylalkyl esters and the amides thereof are derived from ammonia, primary C 1 -C 6  alkyl amines, secondary C 1 -C 6  dialkyl, and 5- and 6-membered heterocyclic amines containing one nitrogen atom; and wherein the group S(═O) 2 M is optionally bonded to the 1-, 2-, or 3-position of Formula I.  
     
     
       6. A method of treating burns, the method comprising administering to a patient having burns a therapeutically effective amount of a compound of Formula I                    
       wherein M is a natural (L) alpha amino acid derivative having the structure                    
       X is O, S, S(O) n , CH 2 , CO, or NR Q ;  
       R Q  is hydrogen, C 1 -C 6  alkyl, or —C 1 -C 6  alkyl-phenyl;  
       R is a side chain of a natural alpha amino acid;  
       R 1  is C 1 -C 5  alkoxy, hydroxy, or —NHOR 5 ;  
       R 2  and R 4  are independently hydrogen, —C 1 -C 5  alkyl, phenyl —NO 2 , halogen, —OR 5 , —CN, —CO 2 R 5 , —SO 3 R 5 , —CHO, —COR 5 , —CONR 5 R 6 , —(CH 2 ) n NR 5 R 6 , —CF 3 , or —NHCOR 5 ;  
       each R 5  and R 6  are independently hydrogen or C 1 -C 5  alkyl; and  
       n is 0 to 2, and the pharmaceutically acceptable salts, esters, and amides thereof, wherein the esters thereof are selected from C 1 -C 6  alkyl esters, C 5 -C 7  cycloalkyl esters, and arylalkyl esters and the amides thereof are derived from ammonia, primary C 1 -C 6  alkyl amines, secondary C 1 -C 6  dialkyl, and 5- and 6-membered heterocyclic amines containing one nitrogen atom; and wherein the group S(═O) 2 M is optionally bonded to the 1-, 2-, or 3-position of Formula I.  
     
     
       7. A method of treating decubital ulcers, the method comprising administering to a patient having decubital ulcers a therapeutically effective amount of a compound of Formula I                    
       wherein M is a natural (L) alpha amino acid derivative having the structure                    
       X is O, S, S(O) n , CH 2 , CO, or NR Q ;  
       R Q  is hydrogen, C 1 -C 6  alkyl, or —C 1 -C 6  alkyl-phenyl;  
       R is a side chain of a natural alpha amino acid;  
       R 1  is C 1 -C 5  alkoxy, hydroxy, or —NHOR 5 ;  
       R 2  and R 4  are independently hydrogen, —C 1 -C 5  alkyl, phenyl —NO 2 , halogen, —OR 5 , —CN, —CO 2 R 5 , —SO 3 R 5 , —CHO, —COR 5 , —CONR 5 R 6 , —(CH 2 ) n NR 5 R 6 , —CF 3 , or —NHCOR 5 ;  
       each R 5  and R 6  are independently hydrogen or C 1 -C 5  alkyl; and  
       R 2  and R 4  are independently hydrogen, —C 1 -C 5  alkyl, phenyl —NO 2 , halogen, —OR 5 , —CN, —CO 2 R 5 , —SO 3 R 5 , —CHO, —COR 5 , —CONR 5 R 6 , —(CH 2 ) n NR 5 R 6 , —CF 3 , or —NHCOR 5 ;  
       each R 5  and R 6  are independently hydrogen or C 1 -C 5  alkyl; and  
       n is 0 to 2, and the pharmaceutically acceptable salts, esters, and amides thereof, wherein the esters thereof are selected from C 1 -C 6  alkyl esters, C 5 -C 7  cycloalkyl esters, and arylalkyl esters and the amides thereof are derived from ammonia, primary C 1 -C 6  alkyl amines, secondary C 1 -C 6  dialkyl, and 5- and 6-membered heterocyclic amines containing one nitrogen atom; and wherein the group S(═O) 2 M is optionally bonded to the 1-, 2-, or 3-position of Formula I.  
     
     
       8. A method of treating chronic ulcers or wounds, the method comprising administering to a patient having chronic ulcers or wounds a therapeutically effective amount of a compound of Formula I                    
       wherein M is a natural (L) alpha amino acid derivative having the structure                    
       X is O, S, S(O) n , CH 2 , CO, or NR Q ;  
       R Q  is hydrogen, C 1 -C 6  alkyl, or —C 1 -C 6  alkyl-phenyl;  
       R is a side chain of a natural alpha amino acid;  
       R 1  is C 1 -C 5  alkoxy, hydroxy, or —NHOR 5 ;  
       R 2  and C 4  are independently hydrogen, —C 1 -C 5  alkyl, phenyl —NO 2 , halogen, —OR 5 , —CN, —CO 2 R 5 , —SO 3 R 5 , —CHO, —COR 5 , —CONR 5 R 6 , —(CH 2 ) n NR 5 R 6 , —CF 3 , or —NHCOR 5 ;  
       each R 5  and R 6  are independently hydrogen or C 1 -C 5  alkyl; and  
       n is 0 to 2, and the pharmaceutically acceptable salts, esters, and amides thereof, wherein the esters thereof are selected from C 1 -C 6  alkyl esters, C 5 -C 7  cycloalkyl esters, and arylalkyl esters and the amides thereof are derived from ammonia, primary C 1 -C 6  alkyl amines, secondary C 1 -C 6  dialkyl, and 5- and 6-membered heterocyclic amines containing one nitrogen atom; and wherein the group S(═O) 2 M is optionally bonded to the 1-, 2-, or 3-position of Formula I.